N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

ABSTRACT

N 2  -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.760,676 filed Jan. 19, 1977 which in turn is a continuation-in-part ofthe following applications:

Ser. No. 707,536 of July 22, 1976, U.S. Pat. No. 4,036,955;

Ser. No. 723,474 of Sept. 14, 1976, U.S. Pat. No. 4,096,255;

Ser. No. 728,051 of Sept. 30, 1976, U.S. Pat. No. 4,104,392;

Ser. No. 671,436 of Mar. 29, 1976, U.S. Pat. No. 4,066,758;

Ser. No. 671,568 of Mar. 29, 1976, U.S. Pat. No. 4,049,645.

Application Ser. No. 671,436 and Ser. No. 671,568 are divisionalapplications of Ser. No. 622,390 of Oct. 14, 1975, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the discovery of certain new and useful N²-arylsulfonyl-L-argininamides and the pharmaceutically acceptable saltsthereof, which are of especial value in view of their outstandingantithrombotic properties and low toxicities.

2. Description of the Prior Art

In the past, there have been many attempts to obtain new and improvedagents for the treatment of thrombosis. The N²-(p-tolysulfonyl)-L-arginine esters have been found to be one type ofagent which can be used and these have been found to be effective indissolving blood clots. (U.S. Pat. No. 3,622,615, issued Nov. 23, 1971).One family of compounds which have been found to be particularly usefulas highly specific inhibitors of thrombin for the control of thrombosisis the N² -dansyl-L-arginine ester or amide. (Our pending U.S.Application Ser. No. 496,939, filed Aug. 13, 1974 now U.S. Pat. No.3,978,045). However, there is a continuing need for a highly specificinhibitor of thrombin for the control of thrombosis, which exhibitslower toxicity.

SUMMARY OF THE INVENTION

It has now been discovered that N² -arylsulfonyl-L-argininamides exhibitantithrombotic activity and even lower toxicity levels at the samerelative potencies, as compared with the N² -dansyl-L-arginine ester oramide.

An N² -arylsulfonyl-L-argininamide having the formula (I): ##STR1## or apharmaceutically acceptable salt thereof, wherein R is ##STR2## whereinR₁ is furfuryl, 3-furylmethyl, tetrahydrofurfuryl ortetrahydro-3-furylmethyl; R₂ is hydrogen, C₁ -C₁₀ alkyl, carboxy, C₂-C₁₀ alkoxycarbonyl, phenyl optionally substituted with one or more C₁-C₅ alkyl, C₁ -C₅ alkoxy or mixtures thereof, C₇ -C₁₂ aralkyl or ringsubstituted benzyl wherein said substituent is C₁ -C₅ alkyl or C₁ -C₅alkoxy; R₃ is hydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or5-indanyl; and n is 0, 1 or 2. ##STR3## wherein R₄ is hydrogen, C₁ -C₁₀alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl; Z is oxy, thio orsulfinyl; and m is 0 or 1, or ##STR4## wherein R₅ is hydrogen, C₁ -C₁₀alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl; p is 0, 1 or 2; q is0, 1 or 2; and p + q is 1 or 2:

and Ar is naphthyl substituted with at least one substituent selectedfrom the group consisting of halo, hydroxy, nitro, cyano, C₁ -C₁₀ alkyl,C₁ -C₁₀ alkoxy and C₂ -C₂₀ dialkyamino, and at least one substituentselected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted withat least one hydroxy, C₁ -C₅ alkoxy or mixtues thereof, naphthylsubstituted with at least one substituent selected from the groupconsisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl,amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl,carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀haloalkyl and phenyl optionally substituted with at least one hydroxy,C₁ -C₅ alkoxy or mixtures thereof;

5,6,7,8-tetrahydronaphthyl substituted with at least one substituentselected from the group consisting of halo, nitro, cyano, hydroxy, C₁-C₁₀ alkyl, C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀alkylthio, C₇ -C₁₂ aralkyl, carboxy, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀carboxylalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀hydroxyalkyl, C₁ -C₁₀ haloalkyl, oxo, and phenyl optionally substitutedwith at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; a phenyl,naphthoquinonly, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl,biphenylenyl, αs-indacenyl, S-indacenyl, acenaphthylenyl,phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl,benzo(b)thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl,dibenzofuranyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl,quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl or benzimidazolyl group any of which isunsubstituted or substituted with one or more groups selected from thegroup consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino carbamoyl, C ₃ -C₁₀N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted withat least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof, or a C₇ -C₁₂aralkyl, C₉ -C₁₆ cycloalkylphenyl, C₁₀ -C₁₈ cycloalkylalkylphenyl, C₉-C₁₆ cycloalkoxyphenyl, C₉ -C₁₆ cycloalkylthiophenyl,9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl,1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl,acenaphthenyl, phenylthiophenyl, 1,2-methylenedioxyphenyl,1,2-ethylenedioxyphenyl, chromanyl, isochromanyl,2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl,2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl,1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl,4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl, or1,2,3,4-tetrahydroisoquinolyl group each of which is unsubstituted orsubstituted with one or more groups selected from the group consistingof halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C.sub. 2-C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl,amino, C₁ -C₁₀ alkylamino, mercapto, C.sub. 1 -C₁₀ alkylthio, C₇ -C₁₂aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀haloalkyl, oxo and phenyl optionally substituted with at least onehydroxy and/or C₁ -C₅ alkoxy.

Also encompassed within this invention are pharmaceutically acceptablesalts thereof.

This invention also relates to a method for inhibiting activity andsuppressing activation of thrombin in vivo in mammals which comprisesadministering to a mammal a pharmaceutically (antithrombotically)effective amount of an N² -arylsulfonyl-L-argininamide or thepharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a group of N² -arylsulfonyl-L-argininamides ofthe formula (I): ##STR5## wherein R is selected from the groupconsisting of ##STR6## wherein R₁ is furfuryl, 3-furylmethyl,tetrahydrofurfuryl or tetrahydro-3-furylmethyl; R₂ is selected from thegroup consisting of hydrogen, alkyl of 1-10 (preferably 1-5) carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,see-butyl, pentyl or the like, carboxy, alkoxycarbonyl of 2-10(preferably 2-5) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl or the like, phenyl optionally substituted with one ormore C₁ -C₅ alkyl, such as methyl, ethyl, propyl, butyl or the like,and/or C₁ -C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy orthe like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such asbenzyl, phenethyl or the like, and ring substituted benzyl wherein saidsubstituent is alkyl of 1-5 (preferably 1-3) carbon atoms, such asmethyl, ethyl, propyl or isopropyl, or alkoxy of 1-5 (preferably 1-3)carbon atoms, such as methoxy, ethoxy, propoxy or isopropoxy; R₃ isselected from the group consisting of hydrogen , C₁ - C₁₀ alkyl, such asmethyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or thelike, C₆ -C₁₀ aryl, such as phenyl, m-tolyl, naphthyl or the like,aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl,phenethyl or the like, and 5-indanyl; and n is an integer of 0, 1 or 2,##STR7## wherein R₄ is selected from the group consisting of hydrogen,C₁ -C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl,octyl, decyl or the like, C₆ -C₁₀ aryl, such as phenyl, m-tolyl,naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms,such as benzyl, phenethyl or the like, and 5-indanyl; Z is selected fromthe group consisting of oxy (--O--), thio (--S--) and sulfinyl (--SO--);and m is an integer of 0 or 1, and ##STR8## wherein R₅ is selected fromthe group consisting of hydrogen, C₁ -C₁₀ alkyl, such as methyl, ethyl,propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ -C₁₀aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12(preferably 7-10) carbon atoms, such as benzyl, phenenyl or the like,and 5-indanyl; p is an integer of 0, 1 or 2; q is an integer of 0, 1 or2; and the sum of p + q is an integer of 1 or 2;

and Ar is naphthyl substituted with at least one substituent selectedfrom the group consisting of halo, hydroxy, nitro, cyano, alkyl of 1-10(preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl orthe like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy,ethoxy, propoxy, butoxy or the like, dialkylamino of 2-20 (preferably2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylaminoor the like, and at least one substituent selected from the groupconsisting of sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10(preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably1-5) carbon atoms, such as methylamino or the like, mercapto, alkylthioof 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio,propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10)carbon atoms, such as benzyl, phenethyl or the like, carboxyl,alkoxycarbonyl of 2- 10 (preferably 2-6) carbon atoms, such asmethoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10(preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl,2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylaminoor the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, suchas acetyl, propionyl, or the like, hydroxyalkyl of 1-10 (preferably 1-5)carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl orthe like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such aschloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like,and phenyl optionally substituted with at least one hydroxy and/or C₁-C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like,naphthyl substituted with at least one substituent selected from thegroup consisting of sulfoamino, carbamoyl, N,N dialkylcarbamoyl of 3-10(preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably1-5)carbon atoms, such as methylamino or the like, mercapto, alkylthioof 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio,propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10)carbon atoms, such as benzyl, phenethyl or the like, carboxyl,alkoxycarbonyl, of 2-10 (preferably 2-6) carbon atoms, such asmethoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10(preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl,2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylaminoor the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, suchas acetyl, propionyl, or the like, hydroxyalkyl of 1-10 (preferably 1-5)carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl orthe like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such aschloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like,oxo and phenyl optionally substituted with at least one hydroxy and/orC₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like,5,6,7,8-tetrahydronaphtyl substituted with at least one substituentselected from the group consisting of halo, nitro, cyano, hydroxy, alkylof 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl,butyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such asmethoxy, ethoxy, propoxy, butoxy or the like, sulfoamino, carbamoyl,N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such asN,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, amino,alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino orthe like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms,such as methylthio, ethylthio, propylthio, butylthio or the like,aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl,phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6)carbon atoms, such a methoxycarbonyl, ethoxycarbonyl or the like,carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such ascarboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylaminosuch as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, suchas acetylamino, propionylamino or the like, alkylcarbonyl of 2-10(preferably 2-6) carbon atoms, such as acetyl, propionyl, or the like,hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such ashydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of1-10 (preferably 1-5) carbon atoms, such as chloromethyl,trifluoromethyl, bromomethyl, 2-chloroethyl or the like, oxo and phenyloptionally substituted with at least one hydroxy and/or C₁ -C₅ alkoxy,such as methoxy, ethoxy, propoxy, butoxy or the like,

a phenyl, naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl,azulenyl, biphenylenyl, as-indacenyl, S-indacenyl, acenaphthylenyl,phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl,benzo(b)thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl,dibenzofuranyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl,quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl or benzimidazolyl group any of which isunsubstituted or substituted with one or more groups selected from thegroup consisting of halo, nitro, cyano, hydroxy, alkyl of 1-10(preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl orthe like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy,ethoxy, propoxy, butoxy or the like, dialkylamino of 2-20 (preferably2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylaminoor the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10(preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably1-5) carbon atoms, such as methylamino or the like, mercapto, alkylthioof 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio,propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10)carbon atoms, such as benzyl, phenethyl or the like, carboxyl,akoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such asmethoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10(preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonyl-amino of1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylaminoor the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, suchas acetyl, propionyl, or the like, hydroxyalkyl of 1-10 (preferably 1-5)carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl orthe like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such aschloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like,and phenyl optionally substituted with at least one hydroxy and/or C₁-C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy, or the like, or aC₇ -C₁₂ aralkyl, such as benzyl, phenethyl or the like. C₉ -C₁₆cycloalkylphenyl, such as cyclopentylphenyl, cyclohexylphenyl,cyclooctylphenyl or the like, C₁₀ -C₁₈ cycloalkylalkylphenyl, such ascyclohexylmethylphenyl, (2-cyclohexylethyl)phenyl,(4-cyclohexylbutyl)phenyl, cyclooctylmethylphenyl or the like, C₉ -C₁₆cycloalkyloxyphenyl, such as cyclopentyloxyphenyl, cyclohexyloxyphenyl,cyclooctyloxyphenyl or the like, C₉ -C₁₆ cycloalkylthiophenyl, such ascyclopentylthiophenyl, cyclohexylthiophenyl, cyclooctylthiophenyl or thelike, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl,9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl,indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl,1,2-methylenedioxyphenyl, 1,2-ethylenedioxyphenyl, chromanyl,isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl,2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl,1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl,4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl, or1,2,3,4-tetrahydroisoquinolyl group each of which is unsubstituted orsubstituted with one or more groups selected from the group consistingof halo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbonatoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10(preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxyor the like, dialkylamino of 2-20 (preferably 2-10) carbon atoms, suchas dimethylamino, diethylamino, dipropylamino or the like, sulfoamino,carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms,such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, amino,alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino orthe like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms,such as methylthio, ethylthio, propylthio, butylthio or the like,aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl,phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6)carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like,carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such ascarboxymethyl, 2 -carboxyethyl, 2-carboxypropyl or the like, acylaminosuch as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, suchas acetylamino, propionylamino or the like, alkylcarbonyl of 2-10(preferably 2-6) carbon atoms, such as acetyl, propionyl, or the like,hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such ashydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of1-10 (preferably 1-5) carbon atoms, such as chloromethyl,trifluoromethyl, bromomethyl, 2-chloroethyl or the like, oxo and phenyloptionally substituted with at least one hydroxy and/or C₁ -C₅ alkoxy,such as methoxy, ethoxy, propoxy, butoxy or the like.

Illustrative of suitable N² -arylsulfonyl-L-argininamides are thoseshown in the table below. In this table, the prior art reference citedin the second column discloses a method of preparation for the compoundlisted in the second column. The Example No. listed in the last columnrefers to an Example of this application which discloses the details ofa method by which the product compound of the fifth column of the tablemay be prepared.

        Product  or salt thereofArSO.sub.2 CL or ArSO.sub.3 H Starting     material      ##STR9##      Pro-rationPrepa- No. (Literature reference) Amino acid ester Ar R     cedure        1      ##STR10##      ##STR11##      ##STR12##      ##STR13##      1  Ber. 31, 1663 2      ##STR14##      ##STR15##      ##STR16##      ##STR17##      1  Ber. 26, 996 3      ##STR18##      ##STR19##      ##STR20##      ##STR21##      3  m.p. 55°      C 4     ##STR22##      ##STR23##      ##STR24##      ##STR25##      3  Helv. chim. Acta., 46, 727 (1963) 5      ##STR26##      ##STR27##      ##STR28##      ##STR29##      2  Ber. 84, 1254 (1956) 6      ##STR30##      ##STR31##      ##STR32##      ##STR33##      2  Zhur. Obschei Khim 22, 866 (1952) 7      ##STR34##      ##STR35##      ##STR36##      ##STR37##      2  Zhur. Obschei Khim 22, 866 (1952) 8      ##STR38##      ##STR39##      ##STR40##      ##STR41##      2  Japanese Patent Published  26975/1964 9      ##STR42##      ##STR43##      ##STR44##      ##STR45##      2  Ber., 86, 951 (1953) 10      ##STR46##      ##STR47##      ##STR48##      ##STR49##      2  Ber., 86, 951 (1953) 11      ##STR50##      ##STR51##      ##STR52##      ##STR53##      2  Zhur Obschei Khim, 30, 1218 (1960)

Also illustrative of suitable N² -arylsulfonyl-L-argininamides are thoseshown in the table below. In this table, the Example No listed in thesixth column refers to the Example of this application by which thecompound in the first column was prepared.

      Compound      ##STR54##      Concentrationrequired toprolong thecoagulationtime by a Preparation     Elementary analysisUpper: Calculated (%) Sample  Addition factor of two     process m.p. Lower: Found (%) I.R. (KBr) No. Ar R moiety (μM) (Ex.     No.) (°      C) C H N (cm.sup.-1)     1      ##STR55##      ##STR56##      -- 8 1 powder 52.7652.68 6.356.21 13.3813.30  3,3603,1601,620 2 "      ##STR57##      1/2 H.sub.2      SO.sub.3  1 134-6 52.2552.07 6.826.73 11.2910.89 3,3603,1801,7401,375 3     "      ##STR58##      -- 0.3 1 powder 53.6253.48 6.566.43 13.0312.98 3,3603,1401,622 4 "      ##STR59##      1/2 H.sub.2      SO.sub.3  1 164-6 52.9852.69 7.006.98 11.0410.86 3,3903,1651,7351,370 5     "      ##STR60##      -- 2 1 powder 53.6253.43 6.566.51 13.0313.12 3,3603,1601,620 6 "      ##STR61##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 52.9852.59 7.006.79 11.0410.89 3,3903,1701,737,370 7 "      ##STR62##      -- 5 1 " 54.4354.38 6.766.79 12.7012.56 3,3503,1801,630 8 "      ##STR63##      1/2 H.sub.2      SO.sub.3  1 195-6 53.6953.40 7.157.12 10.8010.56 3,3803,1801,7381,375 9     "      ##STR64##      -- 1.5 1 powder 55.2154.98 6.957.02 12.3812.47 3,3603,2001,622 10 "      ##STR65##      1/2 H.sub.2      SO.sub.3  1 198-200 54.3754.30 7.307.27 10.5710.36 3,3603,1601,7301,368     11 "      ##STR66##      --  1 powder 56.6456.41 7.307.17 11.8011.51 3,3603,1801,620 12 "      ##STR67##      1/2 H.sub.2      SO.sub.3  1 172-174 55.6455.31 7.597.63 10.1410.18 3,3803,1801,7401,375     13 "      ##STR68##      -- 0.5 3 powder 51.2050.93 6.176.02 12.9812.63 3,3803,1801,630 14 "      ##STR69##      ##STR70##      1.5 3185 47.6747.64 4.924.81 11.1211.12 3,3753,2001,740 15 "      ##STR71##      -- 2.5 3 powder 52.0752.21 6.376.04 12.6712.51 3,3803,2001,620 16 "      ##STR72##      --  3 " 53.6953.53 6.766.69 12.0412.38 3,3803,2001,740 17 "      ##STR73##      -- 2.5 1 " 52.9052.71 6.576.43 12.3412.46 3,3503,1601,640 18 "      ##STR74##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 52.4052.16 6.967.13 10.5410.28 3,3403,1601,736,380 19 "      ##STR75##      -- 5 1 " 52.0751.91 6.376.19 12.6512.38 3,3603,1601,620 20 "      ##STR76##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 51.6851.43 6.826.66 10.7610.58 3,3803,1601,740,37021 "      ##STR77##      -- 4 1 " 52.9052.59 6.576.41 12.3412.16 3,3603,160 1,640 22 "      ##STR78##      1/2 H.sub.2                                                             1      SO.sub.3  1 powder 52.9852.73 7.007.00 11.0410.82 3,9773,160,7401,368     23      ##STR79##      ##STR80##      -- 4 4 " 51.2051.31 6.176.01 12.9812.67 3,3603,1801,610 24 "      ##STR81##      ##STR82##       4 225-7 47.6747.62 4.924.84 11.1211.18 3,3753,2001,742 25 "      ##STR83##      -- 2 1 powder 53.6253.58 6.566.48 13.0312.94 3,3803,2001,630 26 "      ##STR84##      1/2 H.sub.2      SO.sub.3  1 224 52.9852.73 7.007.00 11.0410.82 3,3603,1601,7401,370 27      ##STR85##      ##STR86##      -- 15 1 powder 52.8952.77 6.576.80 12.3412.59 3,3803,2001,625 28 "      ##STR87##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 52.3952.10 6.976.84 10.5410.21 3,3703,1501,740,370 29 "      ##STR88##      --  1 powder 55.2055.00 6.956.81 12.3812.21 3,3603,1501,620 30 "      ##STR89##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 54.3654.25 7.307.11 10.5710.81 3,3703,2001,735,370 31      ##STR90##      ##STR91##      -- 0.5 1 " 54.4354.21 6.556.50 13.8013.79 3,3603,1801,632 32 "      ##STR92##      1/2 H.sub.2      SO.sub.3  1 " 53.6353.50 7.006.79 11.5811.40 3,3803,2001,7401,370 33 "      ##STR93##      --  1 " 51.8651.64 6.136.09 13.7513.84 3,3703,2001,625 34 "      ##STR94##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 55.2155.11 6.956.76 12.3812.27 3,3803,1801,738,368 35      ##STR95##      ##STR96##      -- 0.5 3 " 51.8651.72 6.136.11 13.7513.63 3,3703,1601,620 36 "      ##STR97##      ##STR98##       3 158-160 47.9447.83 4.854.80 11.5111.43 3,3753,2001,740 37 "      ##STR99##      --  1 powder 53.5353.40 6.336.21 14.1914.04 3,3753,1501,620 38 "      ##STR100##      1/2H.sub.2      SO.sub.3  1 " 52.8652.77 6.836.66 11.8611.75 3,3803,2001,7401,370 39 "      ##STR101##      -- 0.5 1 " 54.4354.22 6.556.31 13.8013.59 3,3803,1501,62040 "      ##STR102##      1/2H.sub.2 SO.sub.3  1 131-137(dec.) 53.6353.40  7.007.10 11.5811.40     3,3803,1601,7501,640 41 "      ##STR103##      --  1 powder 55.2655.21 6.766.65 13.4313.29 3,3501,630 42 "      ##STR104##      1/2H.sub.2 SO.sub.3  1 169-175(dec.) 54.3554.27 7.177.00 11.3211.08     3,3503,1801,7401,640 43      ##STR105##      ##STR106##      -- 2.5 1 powder 51.8651.77 6.136.00 13.7513.72 3,3653,2001,62044 "      ##STR107##      1/2H.sub.2                                                              1      SO.sub.3  1 " 51.47 51.20 6.656.35 11.5411.24 3,3703,2001,740,37045 "      ##STR108##      --  1 " 54.4354.28 6.556.31 13.8013.70 3,3753,2001,62246 "      ##STR109##      1/2H.sub.2      SO.sub.3  1 " 53.6353.53 7.007.08 11.5811.40 3,3803,2001,7401,370 47 "      ##STR110##      --  1 " 52.7652.47 6.356.01 13.3813.09 3,3753,1801,620 48 "      ##STR111##      1/2H.sub.2                                                              1      SO.sub.3  1 " 52.2452.00 6.826.55 11.28 11.00 3,3803,2001,740,368 49      ##STR112##      ##STR113##      0.5 H.sub.2 SO.sub.3  1 189-191(dec.) 55.6855.36 6.336.35 10.4710.45     3,3603,1601,730 50 "      ##STR114##      -- 2.5 1 powder 56.7356.43 5.825.80 12.2512.19 3,3703,2001,615 51 "      ##STR115##      ##STR116##       1 132-135(dec.) 52.7852.61 5.175.15 10.2610.23 3,3603,1801,720 52 "      ##STR117##      -- 10 1 powder 57.4257.19 6.026.10 11.9611.73 3,3603,1601,62053 "      ##STR118##      ##STR119##       1 157-158(dec.) 52.7852.63 5.175.14 10.2610.09 3,3803,2201,750 54 "      ##STR120##      -- 3.0 1 powder 57.4257.09 6.026.06 11.9611.74 3,3603,2001,590 55 "      ##STR121##      ##STR122##       1 155-157(dec.) 53.2553.13 5.305.21 10.1110.03 3,3803,1801,720 56 "      ##STR123##      -- 50 1 powder 58.0857.93 6.226.04 11.6811.54 3,200-3,380(broad)1,620     57      ##STR124##      ##STR125##      ##STR126##       1 153-156(dec.) 52.2852.14 5.034.98 10.4110.36 3,4003,0801,740 58 "      ##STR127##      -- 6.5 1 powder 56.7356.58 5.825.73 12.2512.14 3,000-3,400(broad) 1,600     59      ##STR128##      ##STR129##      ##STR130##       1 144-148(dec.) 53.6753.69 5.265.24 10.4310.39 3,3603,2001,720 60 "      ##STR131##      -- 50 1 powder 59.0459.14 6,196.15 12.3012.28 3,040-3,360(broad)1,610     61 "      ##STR132##      ##STR133##       1 155-158(dec.) 53.1954.97 5.125.06 10.59 10.48 3,4003,2001,730 62 "      ##STR134##      -- 15 1 powder 58.3758.19 6.005.98 12.6112.49 3,300 (broad)1,640 63      ##STR135##      ##STR136##      ##STR137##       1 147-150(dec.) 59.1959.23 5.125.07 10.5910.54 3,4001,2301,750 64 "      ##STR138##      -- 20 1 powder 58.3758.21 6.005.93 12.6112.46 3,200 (broad)1,620 65      ##STR139##      ##STR140##      --  1 " 60.2960.21 6.586.56 11.7211.64 3,3653,1701,730 66 "      ##STR141##      -- 2.0 1 " 57.6657.48 5.775.74 12.9312.84 3,3603,1601,610 67      ##STR142##      ##STR143##      -- 1 1 " 50.2550.45 5.956.01 13.3213.15 3,3501.6201,3801,150 68      ##STR144##      ##STR145##      1/2H.sub.2      SO.sub.3  1 " 50.4350.57 6.656.58 10.5010.71 3,3501,7451,6501,360 69 "      ##STR146##      -- 5 1 171-2 50.6050.51 6.196.30 12.2912.40 3,4001,6351,2601,160 70 "      ##STR147##      --  2 powder 55.4055.65 6.626.81 12.4312.19 3,2201,7501,640 71      ##STR148##      ##STR149##      -- 5 2 powder 53.8253.66 6.215.96 13.0812.81 3,3501,6251,155 72      ##STR150##      ##STR151##      ##STR152##       2 192-193 49.58 49.24 4.874.70 11.5611.85 3,2101,7471,638 73 "      ##STR153##      -- 3 2 powder 54.6456.88 6.186.31 13.8513.83 3,200 (broad)1,6201,150 74      ##STR154##      ##STR155##      -- 0.4 2 " 54.6354.50 6.426.09 12.7412.81 3,3701,6251,158 75      ##STR156##      ##STR157##      ##STR158##       2 188-190 50.1750.01 5.034.78 11.3811.56 3,2001,7401,635 76      ##STR159##      ##STR160##      -- 0.15 2 powder 55.4755.49 6.406.33 13.9813.51 3,250 (broad)1,625 77      ##STR161##      ##STR162##      --  2 " 57.0256.81 6.816.91 12.7912.78 3,2001,7401.635 78      ##STR163##      ##STR164##      --  2 powder 55.4755.31 6.406.68 13.4813.21 3,3501,6201,150 79      ##STR165##      ##STR166##      ##STR167##       2 222-3 49.8249.57 5.094.88 11.9911.68 3,2001,7451,630 80 "      ##STR168##      -- 0.35 2 powder 54.6354.55 6.426.42 12.7412.58 3,350 (broad)1,6201,150     81      ##STR169##      ##STR170##      ##STR171##       2 154-6 50.9251.28 5.375.21 10.6610.59 3,4001,7351,635 82 "      ##STR172##      --  2 powder 56.1356.11 6.806.85 12.1211.95 3,300 (broad)1,6101,255 83      ##STR173##      ##STR174##      ##STR175##       2 179-180 50.3850.34 5.235.18 10.8211.05 3,3801,7351,635 84 "      ##STR176##      --  2 powder 55.4055.71 6.626.48 12.4312.53 3,3601,6201,150 85      ##STR177##      ##STR178##      ##STR179##       2 125(soften) 50.7350.58 5.185.11 11.1910.93 3,3801,7351,638 86 "      ##STR180##      --  2 powder 56.2656.41 6.616.48 13.1213.27 3,3601,6201,158 87      ##STR181##      ##STR182##      --  2 " 57.5057.56 7.157.08 11.5611.71 3,3302.9601,7401,640 88 "      ##STR183##      -- 0.5 2 " 56.1356.11 6.806.81 12.1211.96 3,4001,620 89 "      ##STR184##      --  2 " 57.5057.15 7.157.21 11.5611.62 3,3602.9601.735 90 "      ##STR185##      --  2 " 56.1356.21 6.806.81 12.1212.03 3,4001,6201,150 91 "      ##STR186##      --  2 " 54.6354.54 6.426.40 12.7412.68 3,3501,6201,150 92 "      ##STR187##      --  2 powder 56.1356.08 6.806.91 12.1212.08 3,2501,7401,640 93      ##STR188##      ##STR189##      --  2 " 57.0256.86 6,816.83 12.7912.68 3,2301,7401,650 94 "      ##STR190##      --  2 " 54.6354.59 6.426.38 12.7412.68 3,2501,6201,160 95      ##STR191##      ##STR192##      ##STR193##       2 161-163 48.9749.05 4.714.73 11.7611.58 3,3401,7381,635 96 "      ##STR194##      --  2 powder 53.8253.68 6.216.08 13.0812.85 3,3701,6351,2551,155 97      ##STR195##      ##STR196##      --  2 " 54.6454.58 6.186.09 13.8513.93 3,3701,6401,2601,155 98      ##STR197##      ##STR198##      ##STR199##       1 165-168(dec.) 51.9451.50 5.645.41 10.3410.10 3,3903,2201,740 99 "      ##STR200##      --  1 powder 56.1356.00 6.816.73 12.1212.01 3,350 (broad)1,640 100 "      ##STR201##      ##STR202##       1 178-181(dec.) 51.9452.24 5.645.60 10.3410.28 3.4003,2001,735 101 "      ##STR203##      --  1 powder 56.1356.28 6.816.59 12.1212.31 3,350 (broad)1,640 102      ##STR204##      ##STR205##      ##STR206##       1 162-165(dec.) 51.4351.28 5.505.21 10.5010.21 3,3703,2001,730 103 "      ##STR207##      --  1 powder 55.4055.28 6.626.32 12.4312.03 3,300 (broad)1,610 (broad)     104      ##STR208##      ##STR209##      ##STR210##       1 158-160(dec.) 52.7552.56 5.565.43 11.0410.97 3,4053,2201,740 105 "      ##STR211##      --  1 powder 56.2656.01 6.616.49 13.1313.21 3,320 (broad)1,640 106      ##STR212##      ##STR213##      ##STR214##       1 160-163(dec.) 52.3352.03 5.605.30 10.6810.28 3,4003,2101,730 107 "      ##STR215##      --  1 powder 57.0257.39 6.816.21 12.7912.38 3,350 (broad)1,620 108      ##STR216##      ##STR217##      ##STR218##       1 152-155(dec.) 52.8352.53 5.735.72 10.5210.29 3,3903,2051,730 109 "      ##STR219##      --  1 powder 57.7357.51 7.007.23 12.4712.28 3,3701,630 110      ##STR220##      ##STR221##      ##STR222##       1 170-172(dec.) 51.4351.09 5.505.45 10.5010.28 3,3803,2201,740 111 "      ##STR223##      -- 5 1 powder 55.4055.30 6.626.28 12.4312.11 3,400-3,200(broad)1,600     112 "      ##STR224##      ##STR225##      1155-158(dec.)51.9452.29 5.645.63 10.3410.00 3,3803,2001,730113"      ##STR226##      --  1 powder 56.1356.40 6.816.61 12.1212.00 3,200-3,400(broad)1,600 114     "      ##STR227##      --  1 " 54.6354.40 6.426.30 12.7412.50 3,200-3,400(broad)1,600 115 "      ##STR228##      ##STR229##       1 165-170(dec.) 50.8150.68 5.585.43 10.6410.31 3,3803,2001,740 116 "      ##STR230##      --  1 powder 54.4354.70 6.766.71 12.7012.35 3,4001,590 117 "      ##STR231##      ##STR232##       1 164-166 51.3351.60 5.715.38 10.4810.25 3,3603,2001,735 118 "      ##STR233##      -- 2.0 1 powder 55.2155.00 6.956.30 12.3812.40 3,400-3,200(broad)1,570     119 "      ##STR234##      ##STR235##       1 168-172 52.7752.54 5.174.98 10.2610.21 3,3803,1801,740 120 "      ##STR236##      -- 2.5 1 powder 57.4257.35 6.025.84 11.9612.00 3,350-3,160(broad)1,600     121 "      ##STR237##      ##STR238##       1 130-135 53.2553.08 5.305.29 10.1110.29 3,4003,2001,730 122 "      ##STR239##      -- 1.5 1 powder 58.0857.84 6.226.13 11.6811.46 3,3603,1601,600 123 "      ##STR240##      ##STR241##       1 158-163(dec.) 51.9551.80 5.645.38 10.3410.30 3,3603,2001,740 124 "      ##STR242##      --  1 powder 56.1455.98 6.816.79 12.1312.35 3,380-3,200 (broad)1,625     125      ##STR243##      ##STR244##      ##STR245##       1 160-163(dec.) 52.4452.39 5.765.58 10.1910.00 3,4003,2001,740 126 "      ##STR246##      -- 4.5 1 powder 56.8456.72 6.996.80 11.8411.76 3,380-3,250(broad)1,595     127      ##STR247##      ##STR248##      ##STR249##       1 160- 165 (dec.) 50.6250.39 5.405.28 11.1711.15 3,4003,2101,740 128 "      ##STR250##      --  1 powder 54.4354.27 6.556.28 13.8013.59 3,2801,590 129      ##STR251##      ##STR252##      -- 5 1" 52.0751.89 6.376.39 12.6512.51 3,3603,2001,600 130      ##STR253##      ##STR254##      -- 20 5 210-213 54.8654.72 7.337.21 14.5414.27 3,3501,630 131      ##STR255##      ##STR256##      --  5 120- 130 55.7355.82 7.527.50 14.1314.01 3,3501,630 132      ##STR257##      ##STR258##      -- 10 5 108-110 52.1552.21 6.886.71 14.4814.52 3,300(broad)1,630 133      ##STR259##      ##STR260##      -- 30 5 powder 58.2358.01 6.456.35 13.5813.46 3,300(broad)1,635 134      ##STR261##      ##STR262##      --  5 powder 58.9658.91 6.666.79 13.2213.15 3,200(broad)1,635 135      ##STR263##      ##STR264##      --  5 " 55.7355.81 7.527.40  14.1314.10 3,300(broad)1,630 136 "      ##STR265##      --  5 170-173 57.5657.41 7.547.39 13.4313.50 3,3351,630 137      ##STR266##      ##STR267##      --  5 powder 56.7856.85 7.357.29 13.8013.71 3,200(broad)1,630 138      ##STR268##      ##STR269##      --  5 " 58.9658.79 6.666.51 13.2213.19 3,300(broad)1,630 139      ##STR270##      ##STR271##      --  5 142-145 49.0748.90 5.495.38 13.6313.42 3,1501,620 140      ##STR272##      ##STR273##      --  5 powder 47.4747.29 5.435.31 12.5812.39 3,1501,630 141      ##STR274##      ##STR275##      --  5 powder 49.0749.12 5.495.28 13.6313.59 3,1501,630 142      ##STR276##      ##STR277##      --  5 123-130 57.0156.88 6.986.71 13.8513.65 3,3001,635 143      ##STR278##      ##STR279##      -- 0.3 5 powder 56.1956.00 6.776.50 14.2514.00 3,3003,1501,630 144 "      ##STR280##      -- 0.2 5 " 53.5353.24 6.336.19 14.1913.99 3,300(broad)1,630 145 "      ##STR281##      --  5 " 60.0959.79 6.166.02 12.9312.61 3,300(broad)1,630 146 "      ##STR282##      -- 14 5 " 58.7358.66 7.016.90 13.1712.91 3,3801,635 147      ##STR283##      ##STR284##      --  5 147-150 52.5952.31 6.106.01 14.6114.33 3,3801,640 148 "      ##STR285##      --  5 powder 57.2356.98 6.61 6.33 13.9113.81 3,300(broad)1,630 149      ##STR286##      ##STR287##      --  5 " 58.6958.79 5.715.55 13.6913.39 3,300(broad)3,1501,630 150 "      ##STR288##      --  5 powder 56.1955.95 6.776.58 14.2513.97 3,190 (broad)1,620 151      ##STR289##      ##STR290##      -- 20 5 130-135 53.5353.28 6.336.19 14.1913.97 3,3501,640 152      ##STR291##      ##STR292##      -- 10 5 152-157 54.4254.28  6.556.32 13.8013.59 3,3501,635 153      ##STR293##      ##STR294##      -- 4 5 powder 55.3655.10 6.976.76 16.1416.07 3,3801,630 154 "      ##STR295##      --  5 " 52,8652.71 6.566.29 16.0816.07 155      ##STR296##      ##STR297##      --  5 powder 50.9050.81 5.905.70 14.1313.89 3,180 (broad)1,630 156      ##STR298##      ##STR299##      --  5 " 59.4159.22 5.955.73 13.33 13.28 3,170 (broad)1,620 157 "      ##STR300##      HCl  6 " 53.1752.89 6.696.52 12.9212.74 158 "      ##STR301##      HCl  6 " 57.6657.31 6.346.14 11.5911.16 159 "      ##STR302##      --  5 " 55.3355.26 6.546.62 14.6714.58 3,200 (broad)1,630 160      ##STR303##      ##STR304##      -- 0.25 1 " 55.4755.75 6.406.19 13.4813.26 3,350 (broad)1,6301,380 161     "      ##STR305##      -- 0.2 5 " 55.0555.28 7.127.00 13.3813.12 3.200 (broad)1,6351,380 162      ##STR306##      ##STR307##      -- 0.2 1 powder 54.2253.98 5.505.55 13.1813.24 3,320 (broad)1,63013,80     163 "      ##STR308##      --  1 " 57.2257.23 6.356.36 11.9212.08 3,400 (broad)1,7401,620 164 "      ##STR309##      --0.15 1 " 53.8253.78 6.216.19 13.0812.86 3,360 (broad)1,6251,380 165 "      ##STR310##      --  1 " 56.8356.95 6.986.83 11.8411.98 3,400 (broad)1,7351,630 166      ##STR311##      ##STR312##      CH.sub.3 CO.sub.2      H  5 " 53.2853.13 6.626.82 13.8113.71 3,320 (broad)1,6301,140 167      ##STR313##      ##STR314##      --  5 " 51.1550.86 5.605.66 12.9712.87 3,320 (broad)1,6301,380 168      ##STR315##      ##STR316##      --  5 " 54.6453.36 6.186.00 13.8513.58 3,350 (broad)1,6401,390 169      ##STR317##      ##STR318##      --  5 " 56.2755.98 6.616.78 13.1213.24 3,350 (broad)1,6301,3801,140 170      ##STR319##      ##STR320##      --  5 " 54.2154.36 6.926.93 13.7413.76 3,300 (broad)1,6251,3801,160 171      ##STR321##      ##STR322##      --  1, 2 " 53.0852.86 6.246.33 12.3812.41 3,300 (broad)1,6401,160 172 "      ##STR323##      --  1 " 56.0255.83 6.976.88 11.2711.28 3,400 (broad)1,7451,620 173      ##STR324##      ##STR325##      -- 0.2 3 " 57.2356.89 6.616.50 13.9113.70 3,390 (broad) 1,625 174  "      ##STR326##      CH.sub.3      COOH  3 " 56.8356.72 6.986.81 11.8411.56 3,400 (broad)1,7351,640 175 "      ##STR327##      -- 0.1 2 " 58.7358.52 7.016.77 13.1713.00 3,380 (broad)1,620 176 "      ##STR328##      1/2H.sub.2      SO.sub.3  2 " 55.9855.69 7.057.21 11.6611.38 3,400 (broad)1,7301,635     177      ##STR329##      ##STR330##      --  3 " 58.7358.81 7.027.03 13.1713.17 3,300 (broad)1,6151,380 178 "      ##STR331##      CH.sub.3 COOH  3 " 58.1357.98 7.327.56 11.3011.28 3,380 (broad)     1,7301,630 179      ##STR332##      ##STR333##      -- 1 3 " 56.4256.38 6.386.52 14.3114.53 3,350 (broad)1,6201,160 180 "      ##STR334##      CH.sub.3      COOH  3 " 56.1356.08 6.806.83 12.1212.12 3,400 (broad)1,7401,630 181      ##STR335##      ##STR336##      -- 0.5 3 " 58.0057.83 6.826.77 13.5313.63 3,350 (broad)1,6201,160 182 "      ##STR337##      CH.sub.3      COOH  3 " 57.5057.61 7.157.11 11.5611.81 3,350 (broad)1,7301,620 183      ##STR338##      ##STR339##      -- 0.35 3 " 55.5855.62 6.616.81 16.21 16.03 3,350 (broad)1,6201,140 184      ##STR340##      ##STR341##      --  3 " 55.9656.12 7.157.28 14.1914.07 3,350 (broad)1,6201,150 185 "      ##STR342##      CH.sub.3      COOH  3 " 55.7455.90 7.457.51 12.0412.18 3,400 (broad)1,7301,625 186      ##STR343##      ##STR344##      --  3 " 54.3854.08 6.215.91 12.6912.39 3,300 (broad)1,625 187      ##STR345##      ##STR346##      --  2 " 52.2552.36 6.035.98 12.7012.51 3,4001,7351,6401,160 188 "      ##STR347##      --  2 " 50.4650.61 5.585.63 13.3813.40 3,3801,6201,3801,155 189 "      ##STR348##      -- 2 3 " 52.0652.31 5.765.81 13.8013.51 3,3201,6201,3901,155 190 "      ##STR349##      --  2 powder 48.9649.13 5.425.38 12.9812.75 3,3501,6201,3801,150 191      ##STR350##      ##STR351##      -- 5 2 " 51.3851.45 5.815.86 13.0313.12 3,3501,6301,2551,150 192      ##STR352##      ##STR353##      --  2 " 49.5049.31 5.345.40 13.7513.68 3,3503,2001,622 193      ##STR354##      ##STR355##      --  2 " 58.2758.45 5.906.03 11.7211.53 3,3501.7401,6401,2601,160 194 "      ##STR356##      -- 2 2 " 57.6257.68 5.705.55 12.0011.73 3,300 (broad)1,6201,2501,150     195 "      ##STR357##      -- 1.5 3 " 56.9357.12 5.495.43 12.3012.14 3,3601,6251,2601,150 196 "      ##STR358##      -- 6.5 1 " 54.6354.28 6.426.21 12.7412.53 3,350 (broad)1,740 197 "      ##STR359##      --  2 powder 53.8654.16 5.925.62 13.0012.70 3,100 (broad)1,620 198 "      ##STR360##      1/2H.sub.2 SO.sub.3  2 " 54.5354.23 6.105.80 9.649.34 1,7201,630 199      ##STR361##      ##STR362##      --  2 " 48.5548.31 4.934.64 11.8011.53 3,300 (broad)1,620 200      ##STR363##      ##STR364##      HCl 2 6 " 54.1053.81 7.327.13 10.18 9.93 3,180 (broad)1,7401,630 201 "      ##STR365##      --  2 " 57.2256.98 6.246.18 11.1211.31 3,3003,1501,7401,650 202 "      ##STR366##      HCl 20 6 " 54.0953.83 6.055.97 10.5110.36 3,2503,1001,7401,640 203 "      ##STR367##      HCl 30 6 " 55.5355.37 6.126.01 10.1210.01 3,3503,1501,7401,650 204      ##STR368##      ##STR369##      -- 4.5 2 powder 48.9649.13 5.425.36 12.9813.01 3,3501,6201,380 205 "      ##STR370##      -- 2.5 2 " 54.6454.63 6.426.56 12.7413.01 3,3602,9401,6201,380 206      ##STR371##      ##STR372##      -- 12 2 " 59.8959.65 4.524.63 11.6411.81 3,3601,6201,2551,150 207 "      ##STR373##      -- 55   " 50.1549.91 6.416.35 14.0413.83 3,2801,620 208 "      ##STR374##      --  2 " 53.8553.61 5.935.76 13.0012.84 3,3201,610 209 "      ##STR375##      -- 2 2 " 57.4257.37 6.025.86 11.9611.74 3,300 (broad)1,600 210      ##STR376##      ##STR377##      --  2 " 57.4157.33 6.035.94 11.9611.73 3,3001,610 211 "      ##STR378##      -- 2.5 2 powder 53.9853.74 5.385.33 11.6611.74 3,350 1,630 212      ##STR379##      ##STR380##      -- 6.5 2 " 52.0652.40 6.386.37 12.6512.73 3,350 (broad)1,620 213 "      ##STR381##      --  2 " 52.0751.95 6.376.27 12.6512.84 3,350 (broad)1,620 214 "      ##STR382##      -- 15 2 " 52.7552.68 6.366.34 13.3813.41 3,380 (broad)1,620 215 "      ##STR383##      --  2 " 50.9750.67 6.586.61 13.7213.39 3,200 (broad)1,610 (broad) 216 "      ##STR384##      1/2H.sub.2 SO.sub.3  2 " 52.0151.77 6.696.50 10.1110.00 1,7251,620 217      ##STR385##      ##STR386##      --  5 " 46.8146.63 6.005.94 14.3714.23 3,4003,3001,630 218      ##STR387##      ##STR388##      --  5 powder 51.3851.24 5.825.79 13.0312.87 3,3803,3001,630 219      ##STR389##      ##STR390##      --  1 powder 52.1552.03 6.886.73 14.4814.68 3,355mx,1 1,6301,3801,305     220      ##STR391##      ##STR392##      2H.sub.2 O 2 2 195-198 50.4250.48 6.546.16 12.2512.31 3,320o1,620 221 "      ##STR393##      1/22H.sub.2 O 15 2 229-233 52.9452.73 6.306.15 12.8712.93 3,3501,620     222      ##STR394##      ##STR395##      .sup.5/8 6.5 1 powder 48.7848.54 5.775.76 12.9313.15 3,3201,6201,390     223      ##STR396##      ##STR397##      --  5 powder 53.76 53.66 5.955.87 13.3313.34 3,3901,6301,2601,160 224      ##STR398##      ##STR399##      --  5 powder 53.7653.66 5.955.83 14.2514.19 3,4003,2001,655 225      ##STR400##      ##STR401##      --  5 powder 46.6246.53 6.386.21 14.3114.43 3,3503,1501,630 226      ##STR402##      ##STR403##      --  5 powder 49.7149.84 7.027.26 13.1813.36 3,250 (broad)3,1501,630 227     "      ##STR404##      --  5 powder 46.2446.31 6.406.53 13.4813.41 3,3203,1501,630 228      ##STR405##      ##STR406##      HCl  1 powder 47.7447.53 6.756.51 14.6514.41 3,3403,1801,640 229      ##STR407##      ##STR408##        1  52.9552.79 6.005.87 13.4313.28 3,3503,1501,620 230 "      ##STR409##        1  53.16 5.64 13.48 231      ##STR410##      ##STR411##        5  40.7140.60 4.954.78 13.1913.03 3,3603,1601,620 232      ##STR412##      ##STR413##      --  3 powder 55.5955.54 6.296.14 12.4712.35 3,3503,1501,625 233      ##STR414##      ##STR415##      --  3 powder 57.4357.26 6.136.04 12.8812.71 3,3503,1301,615 234      ##STR416##      ##STR417##      --  5 powder 46.8046.61 6.116.05 15.1615.23 3,3753,1501,630 235      ##STR418##      ##STR419##      --  3 powder 50.8250.71 6.866.69 12.8912.57 3,3603,1201,620

The pharmaceutically acceptable salts of the above compounds are ofcourse also included within the scope of this invention. For thepreparation of the compounds of this invention, various methods can beemployed depending upon the particular starting materials and/orintermediate involved. Successful preparation of these compounds ispossible by way of several synthetic routes which are outlined below.

(a) Condensation of an L-argininamide with an arylsulfonyl halide

This process may be illustrated as follows: ##STR420##

In the above formulas, R and Ar as defined herein above; X is halogen;R'" is a protective group for the α-amino group, such asbenzyloxycarbonyl or tert-butoxycarbonyl; R' and R" are selected fromthe group consisting of hydrogen and protective groups for the guanidinogroup, such as nitro, tosyl, trityl, oxycarbonyl and the like; and atleast one of R' and R" is a protective group for the guanidino group.

The N² -arylsulfonyl-L-argininamide (I) is prepared by the condensationof an L-argininamide (VI) with a substantially equimolar amount of anarylsulfonyl halide (VII), preferably a chloride.

The condensation reaction is generally effected in a suitablereaction-inert solvent in the presence of an excess of a base, such asan organic base (triethylamine, pyridine) or a solution of an inorganicbase (sodium hydroxide, potassium carbonate), at a temperature of 0° C.to the boiling temperature of the solvent for a period of 10 minutes to15 hours. The preferred solvents for the condensation includebenzenediethyl ether, diethyl ether-water and dioxane-water. After thereaction is complete, the formed salt is extracted with water, and thesolvent is removed by such standard means as evaporation under reducedpressure to give the N² -arylsulfonyl-L-argininamide (I), which can bepurified by trituration or recrystallization from a suitable solvent,such as diethyl ether-tetrahydrofuran, diethyl ether-methanol andwater-methanol, or may be chromatographed on silica gel.

The L-argininamides (VI) starting materials required for thecondensation reaction can be prepared by protecting the guanidino andα-amino groups of L-arginine (II) via nitration, acetylation,formylation, phthaloylation, trifluoroacetylation,p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation,tert-butoxycarbonylation or tritylation and then condensing the formedN^(G) -substituted-N² -substituted-L-arginine (III) with a correspondingamino acid derivative (IV) by such a conventional process as the acidchloride method, azide method, mixed anhydride method, activated estermethod or carbodiimide method, and thereafter selectively removing theprotective groups from the formed N^(G) -substituted-N²-substituted-L-argininamide (V). The amino acid derivatives (IV) whichare the starting materials for the preparation of the N^(G)-substituted-N² -substituted-argininamides (V) are represented by thefollowing formulas: ##STR421##

In the above formulas, R₁, R₂, R₃, R₄, R₅, n, m, p and q are as definedherein above.

The amino acid derivatives of the above formula (VIII) can be preparedby the condensation of a haloacetate, 3-halopropionate or 4-halobutyratewith an appropriate amine having the formula R₁ NH₂. (See, J. Org.Chem., 25 728-732 (1960)).

The condensation reaction is generally carried out without a solvent orin a solvent, such as benzene or ether, in the presence of an organicbase, such as triethylamine or pyridine, at a temperature of 0° C. to80° C. for a period of 10 minutes to 20 hours. After the reaction iscomplete, the formed amino acid derivative is separated by suchconventional means as extraction with a suitable solvent or evaporationof the reaction solvent and thereafter purified by distillation underreduced pressure.

Among the amino acid derivatives, amino acid tert-butyl esterderivatives are preferred, because they are easily converted to otherester derivatives by acidolysis in the presence of a correspondingalcohol employing an inorganic acid (HCl, H₂ SO₄, etc.) or an organicacid (toluenesulfonic acid, trifluoroacetic acid, etc.). Thearylsulfonyl halides (VII) which are the starting materials for thepreparation of the N² -arylsulfonyl-L-argininamides (I) can be preparedby halogenating the requisite arylsulfonic acids or their salts, e.g.,sodium salts, by conventional methods well known to those skilled in theart.

In practice, halogenation is carried out without a solvent or in asuitable solvent e.g., halogenated hydrocarbons or DMF in the presenceof a halogenating agent, e.g., phosphorous oxychloride, thionylchloride, phosphorous trichloride, phosphorous tribromide or phosphorouspentachloride, at a temperature of -10° C. to 200° C. for a period of 5minutes to 5 hours. After the reaction is complete, the reaction productis poured into ice water and then extracted with a solvent such asether, benzene, ethyl acetate, chloroform or the like.

The arylsulfonyl halide can be purified by recrystallization from asuitable solvent such as hexane, benzene or the like.

(b) Removal of the N^(G) -substituent from an N^(G) -substituted-N²-arylsulfonyl-L-argininamide

This process may be illustrated as follows: ##STR422## In the aboveformulas, R, Ar, X, R', R" and R'" are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by removing theN^(G) -substituent from an N^(G) -substituted-N²-arylsulfonyl-L-argininamide (XII) by means of acidolysis orhydrogenolysis.

The acidolysis is generally effected by contacting the N^(G)-substituted-N² -arylsulfonyl-L-argininamide (XII) and an excess of anacid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide ortrifluoroacetic acid, without a solvent or in a solvent, such as anether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol) oracetic acid at a temperature of -10° C. to 100° C., and preferably atroom temperature for a period of 30 minutes to 24 hours.

The products are isolated by evaporation of the solvent and the excessacid, or by trituration with a suitable solvent followed by filtrationand drying.

Because of the use of the excess acid, the products are generally theacid addition salts of the N² -arylsulfonyl-L-argininamides (I), whichcan be easily converted to a free amide by neutralization. The removalof the nitro group and the oxycarbonyl group, e.g., benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, is readily accomplished by the hydrogenolysis.At the same time, the benzyl ester moiety which can be included in the Rgroup is converted to the carboxyl group by the hydrogenolysis.

The hydrogenolysis is effected in a reaction-inert solvent, e.g.,methanol, ethanol, tetrahydrofuran or dioxane, in the presence of ahydrogen-activating catalyst, e.g., Raney nickel, palladium, orplatinum, in a hydrogen atmosphere at a tempetature of 0+ C. to theboiling temperature of the solvent for a period of 2 hours to 120 hours.

The hydrogen pressure is not critical, and atmospheric pressure issufficient.

The N² -arylsulfonyl-L-argininamides (I) are isolated by filtration ofthe catalyst followed by evaporation of the solvent.

The N² -arylsulfonyl-L-argininamides can be purified in the same manneras described above.

The N^(G) -substituted-N² -arylsulfonyl-L-argininamides (XII) startingmaterials can be prepared by condensing an N^(G) -substituted-N²-substituted L-arginine (III) (generally the N^(G) -substituent is nitroor acyl, and the N² -substituent is a protective group for the aminogroup, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) anda corresponding amino acid derivative (IV), selectively removing onlythe N² -substituent of an N^(G) -substituted-N² -substitutedL-argininamide (V) by means of catalytic hydrogenolysis or acidolysis,and then condensing the thus obtained N^(G) -substituted-L-argininamide(XI) with an arylsulfonyl halide (VII), preferably a chloride in thepresence of a base in a solvent. These reaction conditions are asdescribed above in the condensation of an L-argininamide with anarylsulfonyl halide, and the removal of the N^(G) -substituent from anN^(G) -substituted-N² -arylsulfonyl-L-argininamide.

(c) Condensation of an N² -arylsulfonyl-L-arginyl halide with an aminoacid derivative

This process may be illustrated as follows: ##STR423## In the aboveformulas, R, Ar and X are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by the condensationof an N² -arylsulfonyl-L-arginyl halide (XIV), preferably a chloridewith at least an equimolar amount of an amino acid derivative (IV). Thecondensation reaction can be carried out without an added solvent in thepresence of a base. However, satisfactory results will be obtained withthe use of a solvent such as basic solvents (dimethylformamide,dimethylacetamide, etc.) or halogenated solvents (chloroform,dichloromethane, etc.).

The amount of the solvent to be used is not critical and may vary fromabout 5 to 100 times the weight of the N² -arylsulfonyl-L-arginyl halide(XIV). Preferred condensation reaction temperatures are in the range offrom -10° C. to room temperature. The reaction time is not critical, butvaries with the amino acid derivative (IV) employed. In general, aperiod of from 5 minutes to 10 hours is operable. The obtained N²-arylsulfonyl-L-argininamide can be isolated and purified in the samemanner as described above.

The N² -arylsulfonyl-L-arginyl halide (XIV) starting materials requiredfor the condensation reaction can be prepared by reacting an N²-arylsulfonyl-L-arginine (XIII) with at least an equimolar amount of ahalogenating agent such as thionyl chloride, phosphorus oxychloride,phosphorus trichloride, phosphorus pentachloride or phosphorustribromide. The halogenation can be carried out with or without an addedsolvent. The preferred solvents are chlorinated hydrocarbons such aschloroform and dichloromethane, and ethers such as tetrahydrofuran anddioxane.

The amount of the solvent to be used is not critical and may vary fromabout 5 to 100 times the weight of the N² -arylsulfonyl-L-arginine(XIII).

Preferred reaction temperatures are in the range of -10° C. to roomtemperature. The reaction time is not critical, but varies with thehalogenating agent and reaction temperature. In general, a period of 15minutes to 5 hours is operable.

The N² -arylsulfonyl-L-arginines (XIII) which are the starting materialsfor the preparation of the N² -arylsulfonyl-L-arginyl halides (XIV) canbe prepared by the condensation of L-arginine (II) with a substantiallyequimolar amount of arylsulfonyl halides (VII), by a method similar tothat described in the condensation of an L-argininamide with anarylsulfonyl halide.

(d) Guanidylation of an N² -arylsulfonyl-L-ornithinamide or an acidaddition salt thereof

This process may be illustrated as follows: ##STR424## In the aboveformulas, R and Ar are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by guanidylating anN² -arylsulfonyl-L-ornithinamide (XV) with an ordinary guanidylatingagent such as an O-alkylisourea, S-alkylisothiourea,1-guanyl-3,5-dimethylphrazole or carbodiimide. The preferredguanidylating agents are the O-alkylisourea and the S-alkylisothiourea.

The guanidylation of the N² -arylsulfonyl-L-ornithinamide (XV) with theO-alkylisourea or S-alkylisothiourea is generally effected in a solventin the presence of a base at a temperature of from 0° C. to the boilingtemperature of the solvent for a period of from 30 minutes to 50 hours.Examples of the preferred bases are triethylamine, pyridine, sodiumhydroxide and sodium methoxide.

The base is used in an amount of 0.01 to 0.1 equivalent to the N²-arylsulfonyl-L-ornithinamide.

Examples of the preferred solvents are water, water-ethanol andwater-dioxane.

After the reaction is complete, the N² -arylsulfonyl-L-argininamide (I)is isolated by evaporation of the solvent followed by removal of theexcess base and the formed salt by a water wash.

It is well recognized in the art that an ester derivative of the N²-arylsulfonyl-L-argininamide (I) wherein R₃, R₄ or R₅ is alkyl, aralkyl,aryl or 5-indanyl, can be prepared from a carboxylic acid derivative ofthe N² -arylsulfonyl-L-argininamide wherein R₃, R₄ or R₅ is hydrogen, bythe conventional esterification methods well known to those skilled inthe art.

It is also well recognized in the art that the carboxylic acidderivative can be prepared from the ester derivative by the conventionalhydrolysis or acidolysis methods. The conditions under whichesterification, hydrolysis or acidolysis would be carried out will beeach apparent to those skilled in the art.

The N² -arylsulfonyl-L-argininamide (I) of this invention forms acidaddition salts with any of a variety of inorganic and organic acids.Some of the N² -arylsulfonyl-L-argininamides containing a free carboxylgroup, wherein R₃, R₄ or R₅ is hydrogen, forms salts with any of avariety of inorganic and organic bases.

The product of the reactions described above can be isolated in the freeform or in the form of salts. In addition, the product can be obtainedas pharmaceutically acceptable acid addition salts by reacting one ofthe free bases with an acid, such as hydrochloric, hydrobromic,hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic,succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like. Ina similar manner, the product can be obtained as pharmaceuticallyacceptable salts by reacting one of the free carboxylic acids with abase, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,triethylamine, procaine, dibenzylamine, 1-ephenamine,N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.

Likewise, treatment of the salts with a base or acid results in aregeneration of the free amide.

As stated above, the N² -arylsulfonyl-L-argininamides, and the saltsthereof of this invention are characterized by their highly specificinhibitory activity in mammals against thrombin as well as by theirsubstantial lack of toxicity, and therefore these compounds are usefulin the determination of thrombin in blood as diagnostic reagents, and/orfor the medical control or prevention of thrombosis.

The compounds of this invention are also useful as an inhibitor ofplatelet aggregation.

The antithrombotic activity of the N² -arylsulfonyl-L-argininamide ofthis invention was compared with that of a known antithrombotic agent,N² -(p-tolylsulfonyl)-L-arginine methyl ester, by determining thefibrinogen coagulation time. The measurement of the fibrinogencoagulation time was conducted as follows:

An 0.8 ml aliguot of a fibrinogen solution, which had been prepared bydissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied byArmour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solutionin the same buffer, and 0.1 ml of a thrombin solution (5 units/ml)supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutionsin an ice bath.

Immediately after mixing, the reaction mixture was transferred from theice bath to a bath maintained at 25° C. Coagulation times were taken asthe period between the time of transference to the 25° C. bath and thetime of the first appearance of fibrin threads. In the cases where nodrug samples were added, the coagulation time was 50-55 seconds. Theexperimental results are summarized in Table 1. The term "concentrationrequired to prolong the coagulation time by a factor of two" is theconcentration of an active ingredient required to prolong the normalcoagulation time 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factorof two for the known antithrombotic agent, N²-(p-tolylsulfonyl)-L-arginine methyl ester, was 1,100μm. The inhibitorsare shown in Table 1 by indicating R and Ar in the formula (I) and theaddition moiety. When a solution containing an N²-arylsulfonyl-L-argininamide of this invention was administeredintravenously into animal bodies, the high antithrombotic activity inthe circulating blood was maintained for from one to three hours.

The halflife for decay of the anti-thrombotic compounds of thisinvention in circulating blood was shown to be approximately 60 minutes;the physiological conditions of the host animals (rat, rabbit, dog andchimpanzee) were well maintained. The experimental decrease offibrinogen in animals caused by infusion of thrombin was satisfactorilycontrolled by simultaneous infusion of the compounds of this invention.

The acute toxicity values (LD₅₀) determined by intraperitonealadministration of substances of formula (I) in mice (male, 20 g) rangefrom about 1,000 to 10,000 milligrams per kilogram of body weight.

Representative LD₅₀ values for the compounds of this invention are shownin the following Table.

    ______________________________________                                             Compound            LD.sub.50 (mg/kg)                                    ______________________________________                                        N.sup.2 -(7-methyl-2-naphthylsulfonyl)-L-                                     arginyl-N-butylglycine   >1,500                                               N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-(2-methoxyethyl)glycine                                                                      1,900-2,400                                          N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-(2-ethoxyethyl)-β-alanine                                                                 660-1,000                                          N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-(2-methoxyethyl)glycine                                                                        660-1,000                                          N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-L-                                    arginyl-N-(2-methoxyethyl)glycine                                                                      2,000                                                N.sup.2 -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-                             L-arginyl-N-(2-methoxyethyl)glycine                                                                    >1,500                                               N.sup.2 -(6,7-dimethyl-1-naphthylsulfonyl)-L-                                 arginyl-N-(2-methoxyethyl)glycine                                                                      >1,500                                               N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-(2-ethylthioethyl)glycine                                                                    >1,000                                               N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-benzylglycine  >1,000                                               N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-benzylglycine  >1,000                                               N.sup.2 -(5-methoxy-1-naphthylsulfonyl)-L-                                    arginyl-N-benzylglycine  >1,000                                               N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-phenethylglycine                                                                             >1,500                                               N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-cyclohexylglycine                                                                            >1,500                                               N.sup.2 -(6,7-dimethoxy-2-naphthylsufonyl)-L-                                 arginyl-N-cyclohexylmethylglycine                                                                      >1,500                                               N.sup.2 -(7-methyl-2-naphthylsulfonyl)-L-                                     arginyl-N-tetrahydrofurfurylglycine                                                                    600                                                  N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-tetrahydrofurfurylglycine                                                                    620                                                  N.sup.2 -(6,7-dimethoxy-2-napthylsulfonyl)-L-                                 arginyl-N-butylalanine   >1,500                                               N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-                                arginyl-N-cyclohexylmethylalanine                                                                      >1,500                                               1-[N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                             arginyl]-2-piperidinecarboxylic acid                                                                   1,500                                                Ethyl [1-N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-                             L-arginyl]-4-methyl-2-piperidinecarboxylate                                                               670-1,000                                         1-[N.sup.2 -(4,6-dimethoxy-2-napthylsulfonyl)-                                L-arginyl]-4-methyl-2-piperidinecarboxylic                                                               670-1,000                                          acid                                                                          1-[N.sup.2 -(1-naphthylsulfonyl)-L-arginyl]-4-                                methyl-2-piperidinecarboxylic acid                                                                       700-1,000                                          1-[N.sup.2 -(5-dimethylamino-1-naphthylsulfonyl)-                             L-arginyl]-2-piperidinecarboxylic acid                                                                   700-1,000                                          4-[N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-L-                                 arginyl]-3-morpholinecarboxylic acid                                                                   >1,000                                               2-[N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                             arginyl]-1,2,3,4-tetrahydroisoquinoline-3-                                                             >1,000                                               carboxylic acid                                                               2-[N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                             arginyl]-1-isoindolinecarboxylic acid                                                                  >1,000                                               ______________________________________                                    

On the other hand, LD₅₀ values for N² -dansyl-N-butyl-L-argininamide andN² -dansyl-N-methyl-N-butyl-L-argininamide are 75 and 70 milligrams perkilogram, respectively. The therapeutic agents in this invention may beadministered to mammals, including humans, alone or in combination withpharmaceutically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard pharmaceutical practice.

For example, the compounds may be injected parenterally, that is,intramuscularly, intravenously or subcutaneously. For parenteraladministration, the compounds may be used in the form of sterilesolutions containing other solutes, for example, sufficient saline orglucose to make the solution isotonic. The compounds may be administeredorally in the form of tablets, capsules, or granules containing suitableexcipients such as starch, lactose, white sugar and the like.

The compounds may be administered sublingually in the form of troches orlozenges in which each active ingredient is mixed with sugar or cornsyrups, flavoring agents and dyes, and then dehydrated sufficiently tomake the mixture suitable for pressing into solid form. The compoundsmay be administered orally in the form of solutions which may containcoloring and flavoring agents. Physicians will determine the dosage ofthe present therapeutic agents which will be most suitable for humans,and dosages vary with the mode of administration and the particularcompound chosen. In addition, the dosage will vary with the particularpatient under treatment.

When the composition is administered orally, a larger quantity of theactive agent will be required to produce the same effect as caused witha smaller quantity given parenterally.

The terapeutic dosage is generally 10-50 mg/kg of active ingredientparenterally, 10-500 mg/kg orally per day. Having generally describedthe invention, a more complete understanding can be obtained byreference to certain specific examples, which are included for purposesof illustration only and are not intended to be limiting unlessotherwise specified.

It is to be understood that the present invention includespharmaceutical compositions containing a compound of the invention as anactive ingredient. Such compositions may be in the forms describedabove. In particular, the invention includes such compositions in unitdose form.

EXAMPLE 1 (A) N² -(2-phenoxathiinylsulfonyl)-L-arginine:

To a well stirred solution of 83.6 g of L-arginine in 80 ml of 10%potassium carbonate solution was added 14.9 g of2-phenoxathiinylsulfonyl chloride in 80 ml of benzene. The reactionmixture was stirred at 60° C. for 5 hours, during which time the productprecipitated. After one hour at room temperature, the precipitate wasfiltered and washed successively with benzene and water to give 11.8 g(54 percent) of N² -(2-phenoxathiinylsulfonyl)-L-arginine.

(B) N² -(2-phenoxathiinylsulfonyl)-L-arginyl chloride:

A suspension of 4.36 g of N² -(2-phenoxathiinylsulfonyl)-L-arginine in20 ml of thionyl chloride was stirred for 2 hours at room temperature.Addition of cold dry diethyl ether resulted in a precipitate which wascollected by filtration and washed several times with dry diethyl etherto give N² -(2-phenoxathiinylsulfonyl)-L-arginyl chloride.

(C) N² -(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycinetert-butyl ester:

To a stirred solution of 4.36 g of N-tetrahydrofurfurylglycinetert-butyl ester in 20 ml of chloroform was carefully added N²-(2-phenoxathiinylsulfonyl)-L-arginyl chloride obtained above. Thereaction mixture was allowed to stand at room temperature for one hour.At the end of this period, the reaction mixture was washed twice with 20ml of saturated sodium chloride solution and evaporated to dryness.

The residue was triturated with a small amount of diethyl ether to givean amorphous solid. This was collected by filtration and reprecipitatedfrom ethanolethyl ether to give 3.5 g (52 percent) of N²-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycinetert-butyl ester.

I.R. (KBr): 3400, 1740, 1630 cm⁻¹

Analysis -- Calcd. for C₂₉ H₃₉ O₇ N₅ S₂.1/2H₂ SO₃ (percent): C, 51.61;H, 5.98; N, 10.38 Found (percent): C, 51.88; H, 6.03; N, 10.51

(D) N²-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine:

To a solution of 3.5 g of N²-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycinetert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HCl-ethylacetate. The reaction mixture was stirred for 5 hours at roomtemperature. At the end of this period, the reaction mixture wasevaporated to dryness. The residue was washed several times with drydiethyl ether and chromatographed on 80 ml of Daiaion® SK 102 ionexchange resin (200-300 mesh, H⁺ form, manufactured by MitsubishiChemical Industries Limited) packed in water, washed with water andeluted with 3% ammonium hydroxide solution.

The fraction eluted from 3% ammonium hydroxide solution was evaporatedto dryness to give 1.2 g (40 percent) of N²-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine as anamorphous solid, I.R. (KBr): 3350, 1640, 1250 cm⁻¹

Analysis--Calcd. for C₂₅ H₃₁ N₇ O₅ S₂ (percent): C, 51.98; H, 5.41; N,12.12 Found (percent): C, 52.13; H, 5.49; N, 12.08

EXAMPLE 2 (A) N²-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine ethylester

To a stirred solution of 2.0 g of N-tetrahydrofurfurylglycine ethylester and 4.0 ml of triethylamine in 50 ml of chloroform, which wascooled in an ice-salt bath, was added in portions N²-(2-phenoxathiinylsulfonyl)-L-arginyl chloride obtained above. Thereaction mixture was stirred overnight at room temperature.

At the end of this period, 50 ml of chloroform was added and thechloroform solution was washed twice with 25 ml of saturated sodiumchloride solution, dried over anhydrous sodium sulfate and evaporated invacuo. The oily residue was washed with ethyl ether to give 4.8 g ofpowdery N²-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine ethylester.

Analysis--Calcd. for C₂₇ H₃₅ O₇ N₅ S₂.1/2H₂ SO₃ (percent): C, 48.34; H,5.41; N, 10.44 Found (percent): C, 48.56; H, 5.46; N, 10.33

(B) N²-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine:

A solution of 4.8 g of N²-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine ethylester in 15 ml of methanol and 15 ml of 2N-NaOH solution was warmed to40° C. and held at that temperature for 10 hours. At the end of thisperiod, the reaction mixture was concentrated and chromatographed on 200ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H⁺ form,manufactured by Mitsubishi Chemical Industries Limited) packed in water,washed with ethanol-water (1:4) and eluted with ethanol-water-NH₄ OH (10: 9 : 1). The main fraction was evaporated to dryness and washed withethyl ether to give 3.2 g (80 percent) of N²-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine as anamorphous solid. I.R. (KBr): 3350, 1640, 1250 cm⁻¹

Analysis--Calcd. for C₂₅ H₃₁ O₇ N₅ S₂ (percent): C, 51.98; H, 5.41; N,12.12 Found (percent): C, 52.25; H, 5.56; N, 12.36

EXAMPLE 3 (A) N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginyl-N-tetrahydrofurfurylglycine benzylester

To a stirred solution of 23 g of N^(G) -nitro-N-²-(tert-butoxycarbonyl)-L-arginine in 300 ml of dry tetrahydrofuran wereadded in turn 10 ml of triethylamine and 10 ml of isobutyl chloroformatewhile keeping the temperature at -5° C. After 15 minutes, to this wereadded 30.4 g of N-tetrahydrofurfurylglycine benzyl esterp-toluenesulfonate, 10 ml of triethylamine and 50 ml of drytetrahydrofuran, and then the mixture was stirred for 15 minutes at -5°C. At the end of this period, the reaction mixture was warmed to roomtemperature. The solvent was evaporated and the residue taken in 400 mlof ethyl acetate, and washed successively with 200 ml of water, 100 mlof 5% sodium bicarbonate solution, 100 ml of 10% citric acid solutionand 200 ml of water. The ethyl acetate solution was dried over anhydroussodium sulfate. Upon evaporation of the solvent, the residue wasdissolved in 20 ml of chloroform, and the solution was applied to acolumn (80 cm × 6 cm) of 500 g of silica gel packed in chloroform.

The product was eluted first with chloroform, and then 3%methanol-chloroform. The fraction eluted from 3% methanol-chloroform wasevaporated to dryness to give 24.0 g (60 percent) of N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginyl-N-tetrahydrofurfurylglycine benzylester in the form of a syrup.

I.R. (KBr): 3250, 1740, 1700, 1630, 1260 cm⁻¹

(B) N^(G) -nitro-L-arginyl-N-tetrahydrofurfurylglycine benzyl esterhydrochloride:

To a stirred solution of 24.0 g of N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginyl-N-tetrahydrofurfurylglycine benzylester in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethylacetate at 0° C. After 3 hours, to this solution was added 200 ml of dryethyl ether to precipitate a viscous oily product.

This was filtered and washed with dry ethyl ether to give 17.5 g ofN^(G) -nitro-L-arginyl-N-tetrahydrofurfurylglycine benzyl esterhydrochloride as an amorphous solid.

(C) N^(G) -nitro-N²-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycinebenzyl ester: To a stirred solution of 2.44 g of N^(G)-nitro-L-arginyl-N-tetrahydrofurfurylglycine benzyl ester hydrochloridein 10 ml of water and 40 ml of dioxane were added in turn 1.26 g ofsodium bicarbonate, and 2.2 g of 3-cyclohexyl-4-methoxyphenylsulfonylchloride at 5° C., and stirring was continued for 3 hours at roomtemperature. At the end of this period, the solvent was evaporated andthe residue dissolved in 100 ml of ethyl acetate, and washedsuccessively with 10 ml of 1N hydrochloric acid solution, 20 ml ofwater, 20 ml of 5% sodium bicarbonate and 10 ml of water.

The ethyl acetate solution was dried over anhydrous sodium sulfate. Uponevaporation of the solvent, the residue was chromatographed on 50 g ofsilica gel packed in chloroform, washed with chloroform and eluted with3% methanol-chloroform. The fraction eluted from 3% methanol-chloroformwas evaporated to give 2.4 g (71 percent) of N^(G) -nitro-N²-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycinebenzyl ester in the form of an amorphous solid.

I.R. (KBr): 3300, 1740, 1640, 1255 cm⁻¹

Analysis-Calcd. for C₃₃ H₄₆ O₉ N₆ S (percent): C, 56.39; H, 6.60; N,11.96 Found (percent): C, 56.51; H, 6.58; N, 12.19

(D) N²-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine

To a solution of 2.4 g of N^(G) -nitro-N²-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycinebenzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml ofwater was added 0.5 g of palladium-black and then the mixture was shakenin a hydrogen atmosphere for 50 hours at room temperature. At the end ofthis period, the ethanol solution was filtered to remove the catalystand evaporated to dryness. The residue was washed several times with dryethyl ether and chromatographed on 80 ml of Daiaion ® SK 102 ionexchange resin (200-300 mesh, H⁺ form, manufactured by MitsubishiChemical Industries Limited) packed in water, washed with water, andeluted with 3% ammonium hydroxide solution. The fraction eluted from 3%ammonium hydroxide solution was evaporated to dryness to give 1.1 g(57%) of N²-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycineas an amorphous solid.

I.R. (KBr). 3400, 2920, 1630, 1250 cm⁻¹

Analysis-Calcd. for C₂₆ H₄₁ N₇ O₅ S₁ (percent): C, 55.00; H, 7.28; N,12.34 Found (percent): C, 54.86; H, 7.28; N, 12.49

EXAMPLE 4 (A) N²-(3-cyclohexyl-4-hydroxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine

A solution of 1.6 g of N²-(3-cyclohexyl-4-ethoxycarbonyloxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycineobtained by a method similar to that described in Example 3, in 10 ml ofmethanol and 10 ml of 1N-NaOH solution was stirred overnight at roomtemperature. The reaction mixture was concentrated and chromatographedon 250 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H⁺ form,manufactured by Mitsubishi Chemical Industries Limited) packed in water,washed with ethanol-water (1 : 4) and eluted with ethanol-water-NH₄ OH(10 : 9 : 1). The main fraction was evaporated to dryness and washedwith ethyl ether to give 1.1 g (78%) of N²-(3-cyclohexyl-4-hydroxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycineas an amorphous solid.

I.R. (KBr): 3350, 1625, 1380, 1150 cm⁻¹

Analysis-Calcd. for C₂₅ H₃₉ O₇ N₅ S₁ (percent): C, 54.23; H, 7.10; N,12.65 Found (percent): C, 54.25; H, 7.08; N, 12.86

Various other N² -arylsulfonyl-L-argininamides or acid addition saltsthereof were synthesized in accordance with the procedures of the aboveexamples, and the test results are summarized in Table 2.

    Table 2      ##STR425##      Concentrationrequired toprolong thecoagulationtime by a Preparation     Physical Elemental analysisUpper: Calculated  Sample  Addition factor of     two process proper- Lower: Found  I.R. (KBr) No. Ar R moiety (μM)     (Ex. No.)  ties C H N (cm.sup.-1)                  1      ##STR426##      ##STR427##       0.7 3  55.0054.86 7.287.28 12.3412.49  3,4002,9201,6301,250 2      ##STR428##      "   3  53.7453.81 6.937.04 11.1910.96 3,4001,7601,6301,220 3      ##STR429##      "   4  54.2354.25 7.107.0812.6512.86 3,3501,6251,3801,150 4      ##STR430##      "  1.5 3  56.3356.39 6.486.52 12.1712.07 3,3501,6401,260 5      ##STR431##      "   3  56.4856.47 6.266.08 13.1413.28 3,3501,6301,3851,160 6      ##STR432##      "   3  57.4457.63 6.125.99 12.8812.76 3,4001,6301,150 7      ##STR433##      "   1  51.7852.13 5.415.49 12.1212.08 3,3501,6401,250 8      ##STR434##      ##STR435##        3  57.2356.95 6.476.45 12.8412.76 3,4001,6301,160 9      ##STR436##      ##STR437##        2  55.4055.27 6.626.81 12.4312.25 3,4001,6301,260 10      ##STR438##      ##STR439##      1/2H.sub.2      SO.sub.3  2  48.3448.56 5.415.46 10.4410.33 3,4001,7401,630

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit of the invention as setforth herein.

What is claimed as new and desired to be secured by letters patent ofthe United States is:
 1. An N² -arylsulfonyl-L-argininamide having theformula (I): ##STR440## or a pharmaceutically acceptable salt thereof,wherein R is ##STR441## wherein R₁ is furfuryl, 3-furylmethyl,tetrahydrofurfuryl or tetrahydro-3-furylmethyl; R₂ is hydrogen, C₁ -C₁₀alkyl, carboxy, C₂ -C₁₀ alkoxycarbonyl, phenyl optionally substitutedwith one or more C₁ -C₅ alkyl, C₁ -C₅ alkoxy or mixtures thereof, C₇-C₁₂ aralkyl or ring substituted benzyl wherein said substituent is C₁-C₅ alkyl or C₁ -C₅ alkoxy; R₃ is hydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl,C₇ -C₁₂ aralkyl or 5-indanyl; and n is 0, 1 or 2, ##STR442## wherein R₄is hydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl;Z is oxy, thio or sulfinyl; and m is 0 or 1, or ##STR443## wherein R₅ ishydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl; pis 0, 1 or 2; q is 0, 1 or 2; and p + q is 1 or 2:and Ar is naphthylsubstituted with at least one substituent selected from the groupconsisting of halo, hydroxy, nitro, cyano, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxyand C₂ -C₂₀ dialkylamino, and at least one substituent selected from thegroup consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl,amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl,carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀haloalkyl and phenyl optionally substituted with at least one hydroxy,C₁ -C₅ alkoxy or mixtures thereof, naphthyl substituted with at leastone substituent selected from the group consisting of sulfoamino,carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino,mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyloptionally substituted with at least one hydroxy, C₁ -C₅ alkoxy ormixtures thereof;
 5. 6,7,8-tetrahydronaphthyl substituted with at leastone substituent selected from the group consisting of halo, nitro,cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃-C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀alkylthio, C₇ -C₁₂ aralkyl, carboxy, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀hydroxyalkyl, C₁ -C₁₀ haloalkyl, oxo, and phenyl optionally substitutedwith at least one hydroxy , C₁ -C₅ alkoxy or mixtures thereof;a phenyl,naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl,biphenylenyl, asindacenyl, S-indacenyl, acenaphthylenyl,phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl,benzo(b)thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl,dibenzofuranyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl,quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl or benzimidazolyl group any of which isunsubstituted or substituted with one or more groups selected from thegroup consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino carbamoyl, C₃ -C₁₀N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted withat least one hydroxy C₁ -C₅ alkoxy or mixtures thereof, or a C₇ -C₁₂aralkyl, C₉ -C₁₆ cycloalkylphenyl, C₁₀ -C₁₈ cycloalkylalkylphenyl, C₉-C₁₆ cycloalkoxyphenyl, C₉ -C₁₆ cycloalkylthiophenyl,9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl,1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl,acenaphthenyl, phenylthiophenyl, 1,2-methylenedioxyphenyl,1,2-ethylenedioxyphenyl, chromanyl, isochromanyl,2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl,2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl,1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl,4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl, or1,2,3,4-tetrahydroisoquinolyl group each of which is unsubstituted orsubstituted with one or more groups selected from the group consistingof halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl,amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl,carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀haloalkyl, oxo and phenyl optionally substituted with at least onehydroxy and/or C₁ -C₅ alkoxy.
 2. The compound of claim 1 wherein said Argroup is substituted with at least one C₁ -C₅ alkoxy, C₁ -C₅ alkyl groupor mixtures thereof.
 3. A method of inhibiting activity and suppressingactivation of thrombin in vivo which comprises administering a mammal apharmaceutically effective amount of a compound of claim 1.